Need to Revisit Step Therapy for ARBs

nn Need to Revisit Step Therapy for ARBs To the Editor: We read with interest the article by Yokoyama et al. (April 2007 issue of JMCP) on the effects of a step-therapy program for angiotensin receptor blockers (ARBs) on antihypertensive medication utilization patterns and the cost of drug therapy. The authors reported a saving of $0.03 per member per month with step-therapy intervention that required the use of an angiotensin-converting enzyme inhibitor (ACEI) prior to an ARB in a health plan population of approximately 1 million. However, we have found the conclusions in the study, as well as the editorial, unbalanced and troubling for several reasons. First, there were several limitations of the study design that would clearly impact the cost-saving results. The authors did outline the limitations. These included the potential costs of member and provider dissatisfaction, pharmacy and prescriber costs associated with requesting a prior authorization or changing to an ARB antihypertensive alternative, costs incurred in visits to the physician to switch therapy, and administrative and resource costs required to run the intervention program. In addition, there were pharmacy costs associated with explaining claim rejections to patients. However, not enough emphasis in the manuscript or accompanying editorial was placed on the fact that rebate contracts on drug costs were not factored into the cost analysis. These significant rebates would neutralize the apparent cost savings for a step-therapy managed care intervention program outlined in this manuscript. This analysis would have helped to present a more balanced case for your readers. Another factor not addressed satisfactorily in the article was the finding that, of the 1,296 patients who attempted to obtain an ARB under the step-therapy intervention, 6.6% did not receive any antihypertensive therapy within 12 months of the index date. Not taking therapy certainly will save money in the short term, but was stopping antihypertensive medication medically and ethically appropriate for these patients? What was their clinical outcome, and were costs incurred for later cardiovascular medications/interventions? Only pharmacy claims data were considered in the article, and the effects of step-therapy intervention on clinical outcomes, including effective blood pressure (BP) control and/or attainment of the JNC 7 (Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) BP goal were excluded. Perhaps more alarming was the accompanying editorial to this article. We have identified several troubling statements and examples of selective literature citing; we have listed a sample below: • The editorial downplays the limitations of the analysis. Despite the manuscript noting many factors that would negatively impact the apparent cost savings, the editorial claims that the savings are “underestimated.” • The editorial incorrectly cites a draft report from the Agency Letters

nn Need to Revisit Step Therapy for ARBs To the Editor: We read with intere st the article by Yokoyama et al. ( April 2007 issue of JMCP) 1 on the effects of as tep-therapy program for angiotensin receptor blockers (ARBs) on antihypertensive medication utilization patterns and the cost of drug therapy.T he authors reported asaving of $0.03 per member per month with step-therapy intervention that required the use of an angiotensin-converting enzyme inhibitor (ACEI) prior to an ARB in a health plan population of approximately 1million. However,we have found the conclusions in the study,aswell as the editorial, 2 unbalanced and troubling for several reasons.
First, therew eres everal limitations of the study design that would clearly impact the cost-saving results. The authors did outline the limitations. These included the potential costs of member and provider dissatisfaction, pharmacy and prescriber costs associated with requesting aprior authorization or changing to an ARB antihypertensive alternative, costs incurred in visits to the physician to switch therapy,and administrative and resource costs required to run the i ntervention program. In addition, therew erep harmacy costs associated with explaining claim rejections to patients. However,n ot enough emphasis in the manuscript or accompanying editorial was placed on the fact that rebate contracts on drug costs weren ot factored into the cost analysis. These significant r ebates would neutralize the apparent cost savings for astep-therapy managed careintervention program outlined in this manuscript. This analysis would have helped to present amorebalanced case for your readers.
Another factor not addressed satisfactorily in the article was the finding that, of the 1,296 patients who attempted to obtain an ARB under the step-therapy intervention, 6.6% did not receive any antihypertensive therapy within 12 months of the index date. Not taking therapy certainly will save money in the short term, but was stopping antihypertensive medication medically and ethically appropriate for these patients? What was their clinical outcome, and werecosts incurred for later cardiovascular medications/interventions? Only pharmacy claims data werec onsidered in the article, and the effects of step-therapy intervention on clinical outcomes, including effective blood pressure( BP) control and/or attainment of the JNC 7( Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) BP goal wereexcluded.
Perhaps morea larming was the accompanying editorial to this article. 2 We have identified several troubling statements and examples of selective literaturec iting; we have listed a sample below: •T he editorial downplays the limitations of the analysis.
Despite the manuscript noting many factors that would negatively impact the apparent cost savings, the editorial claims that the savings are"underestimated." •T he editorial incorrectly cites adraft report from the Agency Letters for Health Research and Quality (AHRQ), "Comparative long-term benefits and harms of ACEIs versus ARBs for treating hypertension," ignoring reported differences in BP efficacy and medication persistence between ACEI and ARBs. The report states that therea re significant differences in several assessments, including BP lowering, frequency of cough, and persistence. This is perhaps an irrelevant point, since this report is only at the draft stage and has serious limitations that still need to be addressed beforeitisfinalized. •T he editorial questions the long-term safety of ARBs, citing the AHRQ report. However,t he report conclusions regard ing long-term differences between ACEIs and ARBs are severely limited by the duration and quality of the studies included, with nearly 70% being of 6m onths' duration or less. •T he report analyses assume that agents within ac lass are equivalent (i.e., ac lass effect) and, therefore, minimize differ ences among the individual agents and disregard evidence-based medicine. For example, both candesartan and irbesartan have demonstrated greater BP-lowering efficacy over losartan in 2w ell-controlled clinical studies at maximum doses, meeting stringent U.S. Food and Drug Administration requirements for superiority claims. 3-5 •T he editorial selectively cites literatureo nm edication adherence for patients receiving ACEIs. Several studies that weren ot cited in the editorial demonstrate significantly higher compliance and lower discontinuation rates with ARBs compared with ACEIs. 6,7 Compliance and adherence arerecognized cost drivers for managed health care. An important point that should be taken into account is that clinical studies with ARBs arem orer ecent than studies with ACEIs, which werec onducted in the 1990s, when the prevalence of metabolic syndrome and type 2d iabetes mellitus was considerably less in the United States. Therea re now data with ARBs in "difficult-to-treat" hypertensive patients 8 that cannot be extrapolated to the older studies with ACEIs in aless severeh ypertensive population. In addition, the change in population risk, with higher failurerates with monotherapy and differences in compliance, make the cost estimates unrealistic.
Hypertension control continues to be at remendous unmet medical need in the United States, with approximately two thirds of the 72 million Americans with high blood pressuren ot meeting recommended target blood pressureg oals. 9,10 ARBs and ACEIs arei ntegral medications in the antihypertensive armamentarium. Although both drug classes inhibit the reninangiotensin aldosterone system, important clinical differences exist between the classes as well as within each class that are important for physicians to consider when trying to optimize carefor individual patients. In light of the asymptomatic nature of hypertension and often lifelong duration of therapy for individuals who have high blood pressure, artificially limiting the important treatment choices for physicians and patients

Disclosures
The author discloses that she completed a fellowship with Novartis Pharmaceuticals Corporation, sponsor of the research discussed in her JMCP article.

The Editors Respond:
We welcome the opinions of Ram and Giles regarding angiotensin receptor blocker (ARB) step-therapy interventions. In general, step-therapy interventions are becoming increasingly common in administration of pharmacy benefits in the United States. The proportion of large employers with step-therapy edits doubled from 22% in 2000 to 44% in 2004. 1

The Authors Respond:
Ram and Giles raised concern about the impact of rebates on net drug cost and program savings. While there would be a loss in manufacturer rebates for the formulary angiotensin receptor blockers (ARBs), these offsets were considered before the step-therapy program was implemented. Rebates would only apply to select ARBs, and at the time of the study, net costs of these agents, including rebates, were higher than the cost of generic angiotensin-converting enzyme inhibitors (ACEIs).
Regarding Ram and Giles comment on the 6.6% of patients who did not receive any antihypertensive therapy within 12 months of the index date, this finding is consistent with analyses of other step-therapy programs as discussed in the article. 1

Disclosures
The author discloses that she completed a fellowship with Novartis Pharmaceuticals Corporation, sponsor of the research discussed in her JMCP article.

The Editors Respond:
We welcome the opinions of Ram and Giles regarding angiotensin receptor blocker (ARB) step-therapy interventions. In general, step-therapy interventions are becoming increasingly common in administration of pharmacy benefits in the United States. The proportion of large employers with step-therapy edits doubled from 22% in 2000 to 44% in 2004. 1

The Authors Respond:
Ram and Giles raised concern about the impact of rebates on net drug cost and program savings. While there would be a loss in manufacturer rebates for the formulary angiotensin receptor blockers (ARBs), these offsets were considered before the step-therapy program was implemented. Rebates would only apply to select ARBs, and at the time of the study, net costs of these agents, including rebates, were higher than the cost of generic angiotensin-converting enzyme inhibitors (ACEIs).
Regarding Ram and Giles comment on the 6.6% of patients who did not receive any antihypertensive therapy within 12 months of the index date, this finding is consistent with analyses of other step-therapy programs as discussed in the article. 1

Disclosures
The author discloses that she completed a fellowship with Novartis Pharmaceuticals Corporation, sponsor of the research discussed in her JMCP article.

The Editors Respond:
We welcome the opinions of Ram and Giles regarding angiotensin receptor blocker (ARB) step-therapy interventions. In general, step-therapy interventions are becoming increasingly common in administration of pharmacy benefits in the United States. The proportion of large employers with step-therapy edits doubled from 22% in 2000 to 44% in 2004. 1 For the 12month period through September 30, 2004, step-therapy protocols were reported by 85% of health maintenance organizations, should not be encouraged; decisions as critical as these deserve responsible, well-balanced analyses and careful, thorough review of the available evidence. references two thirds of pre ferred provider o rganizations, 79% of Medicaid plans, and about one half of Medicare-risk plans. 2 Hence, there is increasing need to measureclinical, service, and cost outcomes of these interventions, the principal point of the editorial by Curtiss in which ac ategorical system to rate step-therapy interventions by the degree of restrictiveness was proposed. 3 This categorical system would clearly define the step-therapy intervention according to variables such as the number of first-line therapies required and the scope and method of attestation required of the prescribers. Regarding specific concerns, Ram and Giles claim that insufficient attention was paid to the effects of rebates on drug cost savings associated with the ARB step-therapy intervention evaluated by Yokoyama et al. 4 Presumably this criticism also applies to Gleason, who reported in the same issue of JMCP even larger drug cost savings from aseparate ARB step-therapy intervention. 5 Of note, Yokoyama included the limitation that rebate contracts could offset some of the estimated drug cost savings. Curtiss, in his editorial, did not mention drug manufacturer rebates because these contracts with pharmacy benefit managers and health plans for ARBs acknowledge and allow the widespread use of step-therapy interventions that requireprior use with an angiotensin-converting enzyme inhibitor (ACEI). 6 Hence, ar ebate of 20%, for example, on ARBs with at ypical managed carep rice of $2.00 per day of therapy still leaves agap of about $1.40 per d ay compared with ag eneric ACEI such as generic benazepril that has am anaged carep rice of $0.40 per day or less. This means that 4t o5p atients can be treated with ag eneric ACEI for the cost of treating 1p atient with an ARB. And, of course, from the patient viewpoint, these rebate contracts provide no compensation to members forced to pay higher copayments for brand drugs compared with generic drugs.

C. Venkata S. Ram, MD, MACP, FACC
We do agree with Ram and Giles that not taking ad rug will produce drug cost savings in the short term, and while we are also curious about the outcomes for the 6.6% of patients who did not receive any antihypertensive therapy within 12 months of the step-therapy intervention, this proportion seems small in the context of results of antihypertensive medication adherence studies. Fewer than 50% of even high-risk patients area dherent on both antihypertensive and lipid-modifying drugs within 3m onths of starting drug therapy and only about one thirda t 6months. 7 Third, Ram and Giles cast doubt on the assertion that savings from the step-therapy intervention wereu nderestimated. However,t he possibility of underestimation of savings is quite clear.Since Yokoyama et al.' sstudy sample was drawn for only a 6-month period, aprogram run for afull year would likely have been applied to many morep atients, producing additional cost savings. Additionally,Y okoyama et al.' sstudy sample was limited to continuously enrolled members, who represented only 76% of the patient population to which the program was actually applied.
Fourth, the editorial is accused of ignoring differences in blood pressurer eduction efficacy.O ne is hard-pressed to find better evidence than independent, expert systematic review of all of the available evidence, and to quote from page 31 of the Agency for Health Research and Quality (AHRQ) executive summary, "(o)verall, therew as no clear difference in the blood pressurelowering efficacy between the two classes of agents, no matter what criteria wereu sed for study inclusion. Because of the heterogeneity in study protocols, quantitative meta-analysis was not performed." Although no systematic review is flawless, the U.S. government AHRQ evidence reviews arew idely respected in most evidence-based medicine circles as one of the least biased, most inclusive, and most accurate reports available. For Ram and Giles to selectively scoop af ew studies from the mass of heterogeneous data reflects an arrow approach; in this case, the forest should be appreciated over the trees.
Although clinical differences may exist within each class particularly with respect to U.S. Food and Drug Administrationapproved indications (some agents areindicated for hypertension alone while others have additional renal or cardiac indications), the clinical profiles sufficiently overlap for the ARBs and ACEIs to validate step-therapy in the absence of individual medical necessity.Asnoted in the AHRQ report (page 11), "The hypothesis that ACEIs and ARBs have clinically meaningful differences in long-term outcomes in individuals with essential hypertension is not strongly supported by the available evidence." 8 Added to the thorough evaluation of evidence presented in the AHRQ report on comparative effectiveness arethe results of retrospective analyses such as Winkelmeyer et al. who found multivariateadjusted 1-year mortality that was not different between ARB and ACEI users among 14,190 Medicareb eneficiaries who received either an ACEI or ARB within 90 days of am yocardial infarction (hazardr atio, 1.04; 95% confidence interval (CI), 0.88-1.22). 9 Regarding the complaint by Ram and Giles that the AHRQ report is presently available only in "draft" form, this is the customaryprocedurefor AHRQ, and readers might consider the confirmatoryconclusion from the final 2006 version of the NICE (National Institute for Health and Clinical Excellence) guidelines for hypertension treatment (page 18): "the GDG (guideline development group) felt that the benefits from ACEIs and angiotensin-II receptor antagonists werec losely correlated and that they should be treated as equal in terms of efficacy (although, because of cost differences, ACEIs should be initiated first)." 10 It is true that adherence and persistence with antihypertensive therapy aren ecessaryt or ealize the anticipated efficacy as measured by intermediate outcomes such as blood pressure reduction as well as the hardendpoints of myocardial infarction and cardiovascular-related death. Ram and Giles proffer 2s tudies to support ac laim of superior adherence with ARBs, one as tudy by Koylan et al. conducted in Tu rkey that was an outlier among the 17 studies evaluated in the AHRQ report on comparative effectiveness. 11 The AHRQ report at page 43 concluded, "With the possible exception of the study by Koylan et al., adherence with ACEIs and ARBs was similar (Table 7)." In the second study cited by Ram and Giles, the lisinopril (ACEI) group had ahigher severity of illness and greater use of concurrent medication such as antihyperlipidemics, antiplatelet agents, and beta-blockers compared with the valsartan (ARB) group, and the adjusted adherence was statistically significant but not practically significant, 89.9% for lisinopril (95% CI, 89.3%-90.6%) versus 90.1% for valsartan (95% CI, 89.0-91.1%). 12 For those who prefer trees rather than the forest, we recommend reading the 72 studies referenced in the 57-page AHRQ report on comparative effectiveness of ACEIs and ARBs and the 79 studies referenced in the 98-page NICE hypertension guideline; ACEIs and ARBs arec linically sufficiently similar to allow step therapy.Artificially limiting clinicians' ability to carefor patients by selectively citing literatures hould be roundly condemned by all; likewise, selectively citing contraryo utlier literaturetosupport frivolous expenditureoncostly medication that fails to provide unique benefits should be also be denounced in the public forum.